Following studies in our laboratory in rodents that demonstrated a rapid desensitization of brain serotonin (5-HT2C) receptors in response to the serotonergic agent, m-chlorophenylpiperazine (m-CPP), and a more variable desensitization of 5-HT2A receptors in response to another serotonergic agonist, the hallucinogen DOI, we found that daily administration of m- CPP to healthy human volunteers led to a rapid development of tolerance, indicated by attenuation of the effects of m-CPP on anxiety, temperature, blood pressure and plasma neuroendocrine measures. In clinical studies of selective serotonin antagonists, the 5-HT3 antagonist, ondansetron, significantly attenuated some of the behavioral and physiological responses to both m-CPP and amphetamine in healthy human volunteers, partially replicating prior studies of ondansetron in rodent and non- human primate models. Further investigations of individuals lacking the genes for monoamine oxidase type A and type B (MAO-A or MAO-B) implicate loss of MAO-A function as being responsible for most of the behavioral and physiological abnormalities found in individuals with combined MAOA/B deficiencies. In other genetic studies, a collaborative study with NCI investigators demonstrated a population (N=315) and familial association between a polymorphism in the D4 dopamine receptor gene and the normal personality trait of Novelty Seeking. This constituted a simultaneously published replication and extension of an Israel group's population study of a smaller group of subjects. In collaborative studies with investigators at the University of Wuerzberg, no abnormalities were found in the coding region of the vesicular monoamine transporter in patients with unipolar depression or bipolar disorder.
